The G protein-coupled receptor GPR30 signalosome - A novel G protein-independent mechanism regulating cAMP signaling and receptor trafficking
Author
Summary, in English
This thesis is dedicated solely to one particular GPCR, GPR30. This receptor is shrouded in uncertainty with contradictory results and opposing views on effectors and subcellular localization. The aim of this thesis was to elucidate the signaling and membrane trafficking of GPR30 in addition to look for any binding partners.
My primary findings were:
(1) GPR30 constitutively internalizes without any need for ligand binding.
(2) GPR30 associates with cytokeratin filaments
(3) GPR30 expression in ER+ breast cancer is a favorable prognostic marker for distant-disease-free survival.
(4) GPR30 confer some constitutive pro-apoptotic signaling but also readily sensitizes the cells to other
apoptotic stimuli.
(5) GPR30 directly associates with RAMP3 in-vivo and in-vitro and RAMP3 expression has an impact on
GPR30 subcellular localization in the murine heart.
(6) GPR30 constitutively form a signalosome with Membrane associated guanylate kinase proteins
(MAGUKs) and A Kinase Anchoring Protein 5 (AKAP5) through its C-terminal PDZ-motif. PKA-RII, which directly binds to AKAP5, is responsible for the attenuation of cAMP in response to cAMP- elevating agents.
Department/s
- Drug Target Discovery
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2014
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2015:2
Full text
Document type
Dissertation
Publisher
Drug Target Discovery
Topic
- Pharmacology and Toxicology
Keywords
- AKAP5
- AKAP
- MAGUK
- cAMP signaling
- constitutive signaling
- signalosome
- GPER
- GPR30
- GPCR
- cytokeratin
- RAMP3
- apoptotic signaling
- breast cancer
- PDZ
- PDZ-ligand
Status
Published
Research group
- Drug Target Discovery
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-7619-082-1
Defence date
9 January 2015
Defence time
13:00
Defence place
Segerfalksalen, Sölvegatan 17, BMC A12, Lund.
Opponent
- Graeme Milligan (Professor)